[17AAG & DMAG: Dosage a tricky issue]
>>Cancer Res. 2005 Dec 1;65(23):11094-100.
Induction of the hypoxia-inducible factor system by low levels of heat shock protein 90 inhibitors.
Ibrahim NO, Hahn T, Franke C, Stiehl DP, Wirthner R, Wenger RH, Katschinski DM.
Cell Physiology Group, Medical Faculty, Martin Luther University Halle, Halle, Germany and Institute of Physiology, University of Zurich, and Center for Integrative Human Physiology, Zurich, Switzerland.
The heterodimeric hypoxia-inducible factor-1 (HIF-1) is involved in key steps of tumor progression and therapy resistance and thus represents an attractive antitumor target. Because heat shock protein 90 (HSP90) plays an important role in HIF-1alpha protein stabilization and because HSP90 inhibitors are currently being tested in clinical phase I trials for anticancer treatment, we investigated their role as anti-HIF-1alpha agents. Surprisingly, low-dose (5-30 nmol/L) treatment of HeLa cells with three different HSP90 inhibitors (17-AAG, 17-DMAG, and geldanamycin) increased HIF-1-dependent reporter gene activity, whereas higher doses (1-3 mumol/L) resulted in a reduction of hypoxia-induced HIF-1 activity. In line with these data, low-dose treatment with HSP90 inhibitors increased and high-dose treatment reduced hypoxic HIF-1alpha protein levels, respectively. HIF-1alpha protein stabilized by HSP90 inhibitors localized to the nucleus. As a result of HSP90-modulated HIF-1 activity, the levels of the tumor-relevant HIF-1 downstream targets carbonic anhydrase IX, prolyl-4-hydroxylase domain protein 3, and vascular endothelial growth factor were increased or decreased after low-dose or high-dose treatment, respectively. Bimodal effects of 17-AAG on vessel formation were also seen in the chick chorioallantoic membrane angiogenesis assay. In summary, these results suggest that dosage will be a critical factor in the treatment of tumor patients with HSP90 inhibitors.<<
Cheers, Tuck |
